AU486830B2 - Benzo-bicyclononene derivatives - Google Patents

Description

79,695 The present invention relates to novel biologically

active tricyclic compounds, to processes for the prepa-

ration of these compounds and to the pharmaceutical

application of these compounds. Particularly the invention

relates to novel benzo(b)bicyclo[3.3.l]nona 3,6(10a)dienes

of the general formula I:

y 7? I and salts thereof, in which R 1 and R2 stand for hydrogen, alkyl or al-- kenyl, an optionally substituted aralkyl

group or an acyl group or

R1 R2 together with the nitrogen atom represent

alheterocyclic 5- or 6-membered ring, and

X and Y stand for hydrogen, hydroxy, halogen,

alkyl or alkoxy of 1-6 carbon atoms,

nitro, trifluoromethyl or an acyloxy

group.

The compounds of the general formula I have valuable

biological activities, particularly anorectic activity.

Preferred compounds in this respect are those in which

R 1 and R 2 stand for hydrogen or methyl and/or the benzo

nucleus has been substituted by 1 or 2 halogen (Cl or Br).

A very convenient starting product in the synthesis

of the compounds of formula I is a substance of the general

formula II:

4 86,83

79 6.9 5 sn

in which X and Y have the meanings indicated previously.

These compounds II may be prepared in the usual manners

starting from an optionally substituted (X and/or Y) P-

tetralone. The tetralone in question, which is commercially available or can be prepared in a known manner from commer-

cially available starting products, is treated with pyrro-

lidine affording the corresponding 2-(pyrrolidino)enamine.

The enamine is then converted with acrolein at low tem-

perature into the corresponding 4-hydroxy-benzo (b)bi- cyclo[3.3.l]nonene-ll-one. Alternatively the tetralone in

question may be reacted directly with acrolein at elevated

temperature in the presence of a tertiary amine such as triethylamine or trimethylamine to give the corresponding

4-hydroxy-benzo(b)bicycloL3.3.1]nonene-11-one directly. The compound of formula II is obtained by tosylation of

the 4-hydroxy group and removal of the tosyloxy group thus

obtained in the usual manner, whereby a double bond is

formed at position 3 of the molecule. The condensation of the 2-tetralone enamine with

acrolein can be carried out at preferred temperatures 0 from -60 to +25 C in a variety of solvents, but best

conditions use a low temperature of -50 to -45 C for the

addition.of acrolein and allow the temperature to increase in a controlled manner to ambient temperature over a period

of up to 3 hours. The alternative direct condensation of the optionally

4 86,8

79.69 5 substituted p-tetralone with.acrolein in the presence of a tertiary amine can be carried out in a variety of sol-

vents at preferred temperatures between 30 to 1200 C, but

preferably at the boiling point of the solvent used.

Starting from a compound of formula II the amines or

amides of the invention can be prepared most conve-

niently and directly by a reductive amination.

This method involves a reaction of the starting ketone

II with formamide, N-alkylformamide, N,N-dialkylformamide

or an amine of the general formula III:

T-' HN III

2

or a salt thereof, in which R and R! have the same meanings as R 1 and R 2 defined before with the exception of an acyl

moiety, in the presence of a reducing agent.

A reducing agent, that is very suitable for this

reaction, is formic acid or a formic acid derivative such

as a salt of formic acid and the amine of formula III. In

the latter case the separate addition of the amine III is

even superfluous. This reaction may be carried out at

elevated temperature, preferably in the range of 80-150 0 C,

and most conveniently at the boiling point of the reaction

mixture.

Other suitable reducing agents in this reaction are

metal hydrides, particularly complex-metal hydrides, such

as lithiumaluminiumhydride, sodiumborohydride, sodiumtri-

methoxyborohydride and diisobutylaluminiumhydride, or an

4 86,83C

79, 6 9 5 alkalimetal, preferably sodium, in an alcohol such as

ethanol or isopropanol, used under reaction conditions

whereby the isolated double bond is not or hardly attacked.

This may be obtained by carrying out the reaction at the

lowest possible temperature and by adding the solution or

suspension of the metal hydride (or sodium) to the reac- tion mixture portion-wise and very slowly instead of the

usual procedure of adding the reaction mixture to the

solution or suspension of the metal hydride. The compounds according to the invention can also be

obtained by a reduction of the imino-moiety of a compound

of the general formula IV:

N 3 Iv

Y

in which X and Y have the aforesaid meanings and R 3 stands

for hydrogen, hydroxy, alkoxy, alkyl (1-6 C) or an optional-

ly substituted aralkyl group. The reduction of the imine IV is carried out under mild

reaction conditions by means of standard procedures for the

reduction of an imino moiety. For example, the reduction

can be carried out by hydrogenation in the presence of a

suitable catalyst such as Raney nickel, Pt or PtO 2 with

a metal hydride, particularly complex-metal hydrides

derived from aluminium or boron, such as lithiumaluminium-

hydride, dissolved or suspended in a suitable liquid such

as ether, with an alkalimetal, preferably sodium, in a

suitable solvent such as ether, benzene or alcohol, or with sodiumamalgam or zinc dust in, for example, sodium-

hydroxide. Obviously the reaction is carried out at the

c 4 86,830

79,695 lowest possible temperature in order to avoid a reduction

of the isolated double bond.

The compounds of the formula IV can be prepared by the reaction of the ketone II with a primary amine of formula III or with hydroxylamine or a hydroxylamine- alkylether in the usual manner.

A third method for the preparation of the compounds

according to the invention is starting from a compound of the general formula:

oH

in which X and Y have the aforementioned meanings.

The hydroxyl-comoounds V are obtained by reduction of

the keto group of the ketone II (into a hydroxyl group). This reduction is carried out at relatively low temperature using suitable reducing agents, preferably

metal hydrides such as sodiumborohydride, diisobutyl-

aluminiumhydride, sodiumtrimethoxyborohydride4 lithium-

aluminiumhydridey-e-e-.

The hydroxyl-compound V can be converted into the corresponding amine in various ways. For example, the said hydroxyl group may be converted into a leaving group, such as a mesyloxy group, a tosyloxy group, a p-bromo-

phenyl- or p-chlorophenyl-sulphonyloxy groupi a 2- tetrahydropyranyloxy group, -ete. and then be reacted with an amine according to the general formula III.

Instead of the conversion of the hydroxyl group into

an abovementioned etherified or esterified hydroxyl group

as leaving group, the hydroxyl group may also be halogenated,

486,83

79,69 5 :or example with PC1 5 PBr 3 SOC12, ete and the halo-

jenated compound thus obtained be converted into the esired compound I by reaction with the amine III. The conversions from a hydroxyl group into an amino

Iroup are well-known and described in any chemical hand- >ook.

The aforesaid primary reactions for the preparation

)f the compounds of the invention may be followed

)y additional reactions for the conversion of a compound a salt, )f formula I into a functional derivative, such as )r for the conversion from one compound of the invention

nto another compound of the invention.

So, it is possible to modify a substituent present

at the phenylnucleus into another substituent within

the definition of X and/or Y. For example, a methoxy

roup may be converted into a hydroxyl group, e.g. by a treating with fused pyridine.HCl in the absence of can solvent or by hydrolysis with HBr; a hydroxy group

Deconverted into an alkoxy group, halogen, or an acyl- 3xy group in a conventional manner. The amines of the invention, unsubstituted or mono-

substituted at the nitrogen atom (R1 and/or R 2 is for hydrogen), may be (ar)alkylated in the usual manner,

example by reacting the compound with an (ar)alkylhalide, of the or by acylating the compound followed by reduction carbonyl group. For the introduction of methyl-groups at the nitrogen

atom the well-known procedure of Eschweiler-Clarke

(reaction with formaldehyde formic acid) or the reaction

4 86,830

79,69 5 with formaldehyde or haloformic esters, followed by reductioi with e.g. sodiumcyanoborohydride is to be preferred.

An acyl derivative of the compounds according to the

invention, in which at least one of the groups R 1 or R2 is hydrogen may be obtained by acylating the compound in

the usual manner, preferably by using an anhydride or acid

halide.

Where an N-formyl derivative I is obtained directly from

one of the aforesaid primary reactions, the amide in

question may be hydrolysed using e.g. potassium or sodium-

hydroxide to obtain the primary amine I. For example,

the reductive amination, in which the ketone II is reacted

with formamide in the presence of formic acid (Leuckart-

Wallach reaction), results in first instance in the N-

formyl derivative I, which derivative can be hydrolysed

to the primary amine I, or reduced to the corresponding

N-methyl compound I.

All these additional conversions which might be carried

out after the aforesaid primary reactions are standard

procedures well-known in the art. As far as specific

reagents have been mentioned in these additional conver-

sions, it may be understood that these reagents can be

replaced by other reagents, well-known in organic

chemistry, having a simular effect as the specific

reagents described.

The preparation of the ketone II used as .starting

product in the present synthesis to a compound of formula

I results in a racemic mixture consisting of two enan-.

4 86.83

79, 6 9 5 tiomers of formula II. This racemic mixture II may be I or the processed into the racemic mixture of formula separate racemic mixture II can be resolved into the the enantiomers II in a conventional manner whereupon

separate enantiomers are converted into an optically active endproduct according to formula I. 11 of The replacement of the oxo group at position introduces the ketone of formula II with an amino group of another asymmetric centre resulting into a mixture is two diastereoisomers I, in which the amino group respect to the present in syn- or anti-position with forms can benzene ring. The separate diastereo-isomeric for be isolated from the mixture in the usual manner, thin-layer example by column chromatography, preparative chromatography and/or fractional crystallisation.

methods As described previously, one of the primary the invention for the preparation of the compounds of of the oxo involves in first instance a reduction hydroxyl- group of the ketone II into the corresponding this reduction results compound. It may be understood that the hydroxyl in a mixture of diastereoisomers, in which This mix- group is present in syn- and in anti-position. of the syn-amino ture can be converted into a mixture I or the mixture can and anti-amino compound of formula hydroxyl be separated into the separate diastereoisomeric the syn- or anti- compounds and then be processed into group, amino compound I. The conversion of the hydroxyl amino group in the for example in syn-position, into an a complete manner described before generally involves

4 86.830

79,6957n5 inversion of the configuration. In other words a syn- hydroxyl compound affords, in general, an anti-amino compound I.

The diastereoisomers, enantiomers and mixtures there- of as well as their preparation are also encompassed by this invention.

The novel compounds of formula I may be isolated from the reaction mixture in the form of pharmaceutical- ly acceptable salts, dependent upon the conditions in which the reaction is carried out. The pharmaceutically accep- table salts may also be obtained by treating the free

base I with an organic or inorganic acid such as HC1,

HBr, HI, H 2 SO4 H3 PO 4 acetic acid, propionic acid, glycollic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citri- acid, benzoic acid( ascorbic acid,

The term "alkyl" used in the definition of X, Y, R 1 and R 2 of the general formula I means a saturated branched

or unbranched hydrocarbon (including cyclo-hydrocarbon)

radical with 1-6 carbon atoms, such as methyl, ethyl, n.propyl, n.butyl, cyclopropyl, methylcyclopropyl, cyclo- butyl, methylcyclobutyl, isopropyl, isobutyl, t.butyl,

n-pentyl, isopentyl,-cyclopentyl and hexyl. The same

applies to the alkyl group present in the term "alkoxy"

used in the definition of X and Y.

By "alkenyl" is meant an unsaturated alkyl group with 2-6 carbon atoms, such as allyl, (2)butenyl, etc. With an "aralkyl group", mentioned in the definition of R 1 and R 2 is meant an alkyl group with 1-6 carbon

4 86,83(

7969 5 atoms, substituted with at least one aromatic group.

Preferably a phenylalkyl group is meant, in which the

alkyl group has 1-4 carbon atoms and in which the phenyl group may optionally be substituted by one or more

hydroxy, halogen, lower alkyl or alkoxy groups (1-4 C),

such as benzyl, phenylethyl, phenylpropyl, phenylbutyl,

l-methyl-l-phenyl-ethyl, or p-anisyl, m- or

p-chloro-benzyl, veratryl, m- or p-methyl-phenethyl,

m- or p-hydroxy-phenethyl,-etc.

An "acyl group" mentioned in the definition of R 1 and

R 2 means a group derived from an aliphatic, araliphatic

or aromatic carboxylic acid. The aliphatic carboxylic

acids cover acids with 1-18 carbon atoms, including a

carbocyclic ring, and particularly those with 1-8 carbon

atoms, such as acetic acid, propionic acid, butyric acid,

iso-butyric acid, valeric acid, hexanoic acid, heptanoic

acid, trimethyl-acetic acid, cyclopentane-carboxylic acid

and cyclohexane-carboxylic acid. The araliphatic or arom-

atic carboxylic acids cover optionally substituted arali-

phatic or aromatic carboxylic acids with 7-18 carbon atoms,

especially the optionally substituted phenyl-carboxylic acids and optionally substituted phenylalkyl-carboxylic

acids, in which the alkyl group contains 1-4 carbon atoms

and may be saturated as well as unsaturated, such as ben-

zoic acid, m- or p-toluic acid, o- or p-chlorobenzoic

acid, p-methoxybenzoic acid, phenyl-acetic acid, phenyl-

propionic acid, cinnamic acid, phenylbutyric acid p-

methylphenyl-acetic acid,-e-te. The acyl group in the term "acyloxy" used in the

definition of X and Y has a similar meaning.

4 86,830

79,69 The heterocyclic five- or six-membered rings, as

mentioned in the definition of R1 and R 2 (together with

the nitrogen atom), are derived from 5- or 6-membered

cyclic amines of the general formula III, such as pyrrole,

pyrrolidine, pyrroline, piperidine, piperazine, imidazole

or morpholine.

The novel compounds according to this invention as well

as the pharmaceutically acceptable salts thereof have, as

already said, valuable anorectic activities. For example

8-chloro-ll-amino-benzo(b)bicyclo[3.3.1]nona-3,6a(1Oa)-

diene.HCl is a potent anorectic agent in several animal

species. In contrast to other known anorectic compounds a

long term oral administration of this compound did not

evoke tolerance to its anorectic effect.

Furthermore an antidepressant effect is indicated by

the overall pharmacological profile of the compounds of

the invention.

The compounds of the invention may be administered

orally or parenterally, in a daily dosage of from 0.005

mg, preferably 0.01 10 mg per kg body weight.

Mixed with suitable auxiliaries the compounds I may

be compressed into solid dosage units, such as pills,

tablets and coated tablets or be processed into capsules.

By means of suitable liquids the compounds I can also

be applied as an injection preparation in the form of

solutions, suspensions or emulsions.

STARTING PRODUCTS

The preparation of benzo(b)bicyclo[3.3.1]nona-3,6a(lOa)-

4 86,83

79,69 5 7 dien-ll-one is described starting from p-tetralone. Other

starting products according to formula II are prepared in

a similar manner.

A. 0-tetralone pyrrolidine enamine A mixture of p-tetralone (500 benzene (3 1) and

pyrrolidine (400 ml) was refluxed under nitrogen for

2 h using a Dean and Stark water separator to collect

the water formed. The reaction mixture was evaporated

to dryness under reduced pressure, venting with

nitrogen at the end of the distillation. The residue

was crystallised from light petroleum to give p-tetra- 0 lone pyrrolidine enamine (680 g; 87%) m.p. 80-83 C.

B. 4-hydroxy-benzo(b)-bicycloL3.3.1jnonen-11-one

B.1. A suspension of p-tetralone pyrrolidine-enamine (100

g) in sodium-dried ether (700 ml) was cooled to -7 C 20 under nitrogen, and a solution of acrolein

ml) in dry ether (50 ml) was added dropwise over

min with stirring, while allowing the temperature to rise to O°C 20 over 45 min.

Further additions of acrolein (25 ml, 15 ml and

ml) in equal volumes of ether were added at hourly

intervals, each addition taking 20 min, keeping the

temperature at O0C 2° throughout. After 5 h, water

(200 ml) was added dropwise while maintaining the

temperature at 0 to 50C. After a further half hour

N hydrochloric acid (100 ml) was added dropwise

to pH 3 6, maintaining the temperature at

20. The product was extracted into methylene

13 4 86,83

79, 69 5 n chloride, (2 x 250 ml) and the extract was washed

with water to pH 7, dried and filtered through

silica gel.

Crystallisation from methylene chloride/ether gave 4-hydroxy-benzo(b)bicyclo[3.3.1Jnonen-11-one (50 g) as a mixture of 4-exo- and endo-hydroxy epimers.

The compound B may also be prepared as follows:

B.2. P-Tetralone pyrrolidine-enamine (100 g) was added to a stirred, freshly prepared solution of acrolein

ml) in methylene chloride (1 1) at -55 to -600 C.

After stirring for 30 min at -60° the temperature of

the solution was allowed to rise to -120 20 C over min. After 1/2 h the reaction temperature was

allowed to rise to -50 over a further 1/2 h (total

reaction time h) and water (100 ml) was added. The organic layer was separated off and washed with

IN hydrochloric acid (3 x 250 ml) and water (2 x 250 ml) to pH 7, and dried. The dried extracts were concentrated, slaked with

ether, and the crude product (76 g) was recrystal-

lised from methanol to give 4 -exo-hydroxy-benzo(b) bicycloL3.3.1Jnonen-ll-one (54 g) m.p. 149-152 0 C.

C. benzo(b)-bicyclo 3 3 .1lnona-3,6a(Oa)-dien-11-one A solution of 4-exo- and 4 -endo-hydroxy-benzo(b)bicyclo L3.3.1]nonan-ll-one (100 g B) in pyridine (250 ml) was cooled with stirring to 5°C e 2° and methane sulphonyl chloride (78 ml) was added dropwise keeping the tem- perature below 10C. Stirring was continued at 50 to

C for a further 1/2 h and the reaction was set aside

14 4 86.83C

79, 69 at this temperature for about 72 h.

The mixture was poured onto ice (8 1) and allowed to

was stand at room temperature for 18 h. The mesylate (500 ml). filtered and dissolved in methylene chloride solution After separation from the excess of water the (140 Recrystal- was dried and evaporated to dryness

lisation from methylene chloride/ether gave the mesylate 0 as prisms (120 g) m.p. 106-107 C. in colli- The mesylate from above (120 g) was dissolved down until the dine (350 ml) and the mixture distilled 0 temperature reached 165-170 C. Heating was continued solution under reflux for a further 5 h and the cooled

was poured into a mixture of ice (5 1) and 5 N hydro-

chloric acid (300 ml). The solid was filtered off,

(250 ml). The solution washed and dissolved in ether and evaporated was washed with water till neutral, dried reduced pressure to dryness. The residue was distilled under

to give benzo(b)bicyclo[3.3.1]nona-3,6a(10a)-dien-11-one,

b.p. 1440/2 mm Hg.

3 (tosyl- D. benzo(b)bicyclo 3 .l1nona-3,6a(O0a)-dien-11-one

oxy route) Toluene-sulphonyl-chloride (175 g) was added in portions

to a stirred solution of 4-exo- and 4-endo-hydroxy- (150 benzo(b)bicycloL3.3.1]nona-3,6a(l0a)diene-11-one 2 After 1/2 g B) in dry pyridine (300 ml) at 5°C the reaction h the temperature was allowed to rise and

was continued at room temperature for 3 days. product was The solution was poured into water and the and filtered off, dissolved in methylene chloride

4 86,830

79,69 washed with 1 N hydrochloric acid, water to pH 7, dried

and evaporated to dryness (260 Crystallisation from methylene chloride/ether gave a sample of the pure

tosylate m.p. 150-151 C. Lithium carbonate (260 g) and

lithium bromide (55 g) were added to a solution of the

tosylate (260 g) in dimethyl acetamide (2.5 1) and the

mixture was slowly distilled over 2 hours, collecting

about 2 litres of distillate. After cooling the residue

was poured into ice and allowed to stand overnight.

The solid was filtered off, digested with ether and the

inorganic residue was removed by filtration. The fil-

trate was washed with water to pH 7, dried and

evaporated to dryness.

The residue was distilled under reduced pressure to give

benzo(b)bicyclo[3 3.1]nona-3,6a(10a)-dien-11-one,

b.p. 130-140°C/1 mm Hg (105 g).

Example I ll-formamido-benzo(b)bicyclo[3.3.1]-nona-3,6a(10a)diene

A solution of benzo(b)bicyclo[3.3.1]-nona-3,6a(10a)-dien- 11-one (102 g) in a mixture of formamide (400 ml) and formic

acid (200 ml) is boiled under reflux for 1 1/2 h and poured

into a mixture of ice and potassium hydroxide solution.

After allowing to stand for 18 h, the solid is filtered

off, dissolved in methylene chloride, washed neutral and

chromatographed to give 11-syn-formamido-benzo(b)bicyclo

[3.3.1]nona-3,6a(10a)-diene (22.5 g) in needles,m.p. 182-

183 C, and ll-anti-formamido-benzo(b)bicyclo[3.3.1]nona-

3,6a(10a)-diene (27.6 m.p. 173-178 0 C.

16 4 86,83

79, 69 5 n Example .II

ll-amino-benzo(b)bicvclof 3 3 .1]-nona-3,6a(10a)-diene.HCl

A solution of ll-syn-formamido-benzo(b)bicyclo[3.3.1] (60 ml) and 10 M nona-3,6a(10a)-diene (6.0 g) in ethanol ml) is boiled under reflux potassium hydroxide solution (6 precipitated by for 4.5 h, concentrated, and the amine with ether addition of an excess of water. Extraction

gives 11-syn-amino-benzo(b)bicyclo[3.3.1]nona-3,6a(lOa)- dissolved in ether and diene (6.5 g) as an oil, which is addition of a solution converted to the hydrochloride by Crystallisation from of hydrogen chloride in ether. methanol gives pure 11-syn-amino-benzo(b)bicyclo[3.3.1] 0 (5.6 g) m.p. >280 C. nona-3,6a(10a)-diene hydrochloride In the same manner the 11-anti-amino-benzo(b)bicyclo is prepared (sublimation 3 3 .l]nona-3,6a.(10a-diene.HCl the corresponding 11- point about 265C) starting from anti-formamido-compound.

Example III

8-methoxy-ll-formamido-benzo(b)bicyclof3.3.llnona-3,6a

A solution of 8-methoxy-benzo(b)bicycloL3.3.1]nona- and (45 g) in formic acid (90 ml) 3 ,6a(lOa)-dien-ll-one reflux for 1 3/4 h, formamide (270 ml) is heated under of ice and 10 N KOH cooled and poured into a mixture and 11-anti-forma- solution to give a mixture of 11-syn- 3 ,6a(10a)-diene mido-8-methoxy-benzo(b)bicyclo[3.3.1]nona-

(43 g) (approx. 45:55). toluene,filtered through The product is dissolved in to give a separa- alumina and carefully chromatographed

4 86,830

79,669 5 tion of the il-epimers. Crystallisation from methylene

chloride/ether of combined fractions gives 8-methoxy-li-

anti-formamido-benzo~b)bicycloL3.3.l]nona-3,6a(loa)-diene

g) m.p. 153-1550, and 8-methoxy-1l-syn-formamido-ben-

zo (b)bicyclo[ 3.3. l]nona-3,6a(l0a)-diene, (14.5 g) m.p.

125-126 0 C.

Example IV

8-chloro-1l-formamido-benzo bicyclo[ 3.3.1 lnona-3, 6a

Cl0a) -diene

8-chloro-benzo(b)bicyclol3.3.1]nona-3,6a(l0a)-diel-

11-one (33 g) is dissolved in a mixture of formic acid

198 ml) and formamide (330 ml) and the solution

refluxed for 3.5 h, cooled, diluted with water and made

alkaline with 5% aqu'-ous sodium carbonate solution. The

mixture is extracted with methylene dichloride, and the

extracts washed neutral with water, dried (MgSO4 and

evaporated to dryness yielding a mixture of 11-anti- and

11snfraio8clr-ez~~iylL..]oa

3,6a(l0a)-diene (37 g) as an oily substance.

Examole V

11-formamido-substituted benzo(b)bicyclo[3.3.l Inona-3,6a -diene

Starting from the desired benzo(b)bicycloL3.3.l]nona-

3,6a(l0a)-dien-ll-one compound substituted at the phenyl

ring with 8-bromo-, 8-hydroxy, 9-chloro, 8, 9-dichloro, 8,10-

dichloro, 8-methyl or 9-CF 3respectively, the follo-

wing 11-formamido compounds are prepared in the same

manner as described in Example I:

870dclr-1fraiobnz~~iyl[..]oa36

1 R iR 4 86,830

79, 69 8 -bromo-11-formamido-benzo(b)bicyclo[3.3.l1nona3,6a(1a)-

diene,

8-hydroxy-11-formanido-benzo(b)bicyclo3.3.ljnona-3,6a

(l0a) -diene, 9-chloro-ll-formamido-benzo bicycloL3.3.1 ]nona-3, 6a (l0a) -diene,

8,9-dichloro-ll-formamido-benzo(b)bicyclol3.3.ljnona-3,6a

(l0a)-diene, 8-methyl---l-formamido-benzo bicycloL 3.3.1 jnona-3, 6a (lOa) diene, 9-trifluoromethyl-l-fo:mamido-benzo(b)bicyclo[3.3.ljriona-

3,6a (l0a)-diene.

Example VI 8-chloro-11-amino-bm-zo(b)bicycloF3.3.llnona-3,6a(10a)-

diene and corresponding N-acetyl derivative The mixture of ll-formaxnido compounds of Example IV

(37 g) is dissolved in ethanol (370 ml) and 10 N aqueous potassium hydroxide solution (37 ml) is added. The solution is refluxed for 4 h, cooled, diluted with water and the

crude product isolated using ether. The epimeric mixture

is treated with hydrogen chloride in ether and the hydro-

chlorides chromatographed and fractionally crystallised

from methanol yielding 8-chloro-ll-anti-amino-benzo (b)

3.3.ljnona-3,6a~lOa)diene bicyclo[. hydrochloride m.p. 21350

(6.7 and 8-chloro-ll-syn-aminio-benzo(b)bicycloL3.3.l] rona-3,6a(10a)-diene hydrochloride m.p. 2500 (5.2 g)9 aLong with a mixture of epimers (9.0 g) in the mother

:_qCors.

Rec Lion of the 11-anti-amino compound with acetyl-

4 86,830

79, 695/75 chloride (1 equivalent) yields the corresponding 8-chloro- 11-anti-acetylamino-benzobbicycloL33.lnona. 3 ,6a(10a)-

diene.

Example VII In the same manner as described in Example VI are

prepared the following compounds: 8, 9 -dichloro-11-syn.amino-.benzo(b)bicycloL 3.3. ljnona-3, 6a

(10a)-diene.HC1, 8, 9 -dichloro-.ll-anti-amino-benzo(b)bicycloL 3.3. ljnona-

-diene.HC1, 9 -trifluoromethyl-11-syn-amino-benzo(b)bicycloL33.ljnona-

3,Ga(lOa)-diene.HCl, 8-bromo-11-anti-amino..benzobbiycloL3.3.ljnona.3,6a~l~a)-

diene.HC1, 9 -chloro-ll-syn-amino-benzo bicycloL 3.*3 1jnona-3, Ga (1a) dieneHC1, 9 -chloro-11-anti-amino-benzo(b)bicyclO[3.3.lnona3,6a(1a)-

diene.HCI, 8-methyl-11-anti-amino-benzo(b)bicyclOL3.3.ljpona-36a(1a)-

diene.HCl, 8 -methyl-11-syn-amino-benzo(bbicycloL3.3.ljnona.3,6a(1a)

diene.HC1, 8 -hydroxy-ll-syn-amino.benzo bicyclo[ 3.3 1jnona-3, 6a Cba) diene.HC1, 8-hydroxy-11-anti-amino-benzylbbicyclo3.3.ljnona. ,6a 3

(10a)-diene.HC1, 9 8, -dimetlhoxy-11-anti-amino.benzo(b)bicycOL33ljnona-

3, 8-chloro-9-Itrifluoromethyl-1ilanti.amino-benzo(b) bicycbo

L3.3. ljnona-3 ,6a(l~a)-diene,

4 8683(

79,69 5

8-chloro-9-trifluoroethyl-1-syn-amino-benzo(b)bicyclo

L3.3.1]nofa-3,6a(10a)-diefe,

8-nitro-9-trifluoromethyl-l-amino-benzo(b)bicyclo

L3.3 .ljnona-3,6a(la)-diene, 8,10-dichloro-11-anti-amino-benzo(b)bicyclo

L3.3.lJnona-3,6a(0a)-diene.HCl.

Example VIII

1lmethylamino-benzo(b)bicyclor3.3.llnona-3,6a(10ea)-diene (9.24 g) in A suspensiorr of lithiumaluminiumhydride

dry tetrahydrofuran (210 ml) is cautiously and dropwise

added to a solution of 1l1syn-formamido-benzo(b)bicyclo

L3.3.1nona-3,6a(l0a)diefe (35.0 g) in 25 ml dioxan and temperature for the resultant mixture stirred at ambient

After addition of water (10 ml), 4 N sodium hours.

hydroxide (9 ml) and water (25 ml) the inorganic solids diluted are filtered off. The filtrate is concentrated, into ether to give with water and the product extracted 3.3.llnona-3,6a crude .1-syn-methylamino-benzo(b) bicyclo

as an oil (35 The oily substance is then

Addition of a chromatographed over a silicagel column.

saturated solution of HCl in ether to an ether solution

a precipitate of of the product chromatographed yields ljnonat6a 11-syn-methylamino-benzo(b)bicyclol3.3 purified by repeated diene.hydrochloride, which is further 0 Melting point >260 C. crystallisation from methanol/ether. salt (HC1) In the same manner the ll-anti-methylamino 0 is obtained (subl. p. 270 C) starting from 11-anti-forma-

mido-benzo(b)bicycioi3.3jnona-3,6a(10a sodiumcyano- The same product can be obtained by using

ohydride instead of LiAlH4

4 86,830

79* 6 9 5 Example IX

1l-dirnetlhylamino--bcnzo(b)b)icycloL 3.3.ljnona-3,6a(loa)-

diene.HCl

A. A solution of 1l-syn-methylamino-benzo(b)bicycloL3.3.l]

nona-3,-6a(l0a)-diene (6.0 g) in a mixture of formic acid

ml) and forrnalin (6.5 ml) is heated at 90-100 0 C for

1 b, diluted with water and a slight excess of potassium

hydroxide solution, and the product is extracted into

ether to give ll-syn-dimethylamino-benzo(b)bicyclo

[3.3.ljnona-3,6a(l~a)-diene as an oil (6.0 g). Treatment with hydrogen chloride in ether and crystal-

lisation from methanol/ether gives 11-syn-dimethyl-

amino-benzo(b)bicycloL3.3.ljnona-3,6a(l0a)-diene hydro- chloride (4.8 m.p. >230 0 C.

In the same manner the corresponding 11-anti-dimethyl-

amino compound is prepared as the HCl salt, m.p. 255 0 C

Csubl.).

B. A mixture of these li-syn- and 11-anti-dimethylamino

compounds is obtained by reacting benzo(b)bicycloL3.3.lj

nona-3,6a(l0a)-dien-ll-one with formic acid and dimethyl-

formamide (instead of formamide) in the same manner as

described in Example I. The mixture is chromatographed

to give the separate isomers as oily compounds. Treat-

ment with HCl yields the separate HCl salts.

Example X

ll-svn-dimethvlamino-benzo(b)bicvcloL3.3.l Inona-3,6a(10a)-

diJene.11Cl and separation of the optical enantiomers

A solution of l1-syn-amino-benzo(b)bicyclo[3.3.ljnona-

3,6a(10a)-diene (2.1 g) in a mixture of formic acid (2.4 ml)

4 8 6,8 E

79, 69 5/75 0 and formalin (1.7 ml) is heat'ed at 90-100 C for 1 h, diluted

with water and a sliqht excess of potassium hydroxide solu-

tion and the product is extracted into ether to give 11-

syn-dimethylamino-belzo bicycloL 3.3.1 jnona-3 ,6a (1a)

diene as an oil (2.1 g).

Treatment with hydrogenchioride and crystallisation of

the product from methanol/ether gives 11-syn-dimethyl-

amino-benzo(b)bicycloL3.3.ljnona-3,6a(10a)-diene-hydro- chloride (1.6 m.p. >2300

The racemic mixture (free base) obtained above is re-

solved in the usual manner using L-tartaric acid and D.-

tartaric acid respectively, resulting in the separate

and form of ll1-syni-dimethylamin0-benzo(b)bicycboL3.3.1l

nona-3,6a(l0a)-diene. The optical enantiomers are converted into their HCl-salts to obtain crystalline compounds.

Example XI 3 3 8-methoxy-11-methlamin-benzo(b)bicyco .l nona-3,6a

(10a)-diene.HC1

8-Methoxy-11-syn-formamido-benz0 bicyclo' 3.3.1 oa

3,6a(l0a)-diele (5.0 obtained in Example III is re-

duced with lithiumaluminiumhYdride as described in -Example VIII to give 8-methoxy-11-syn-methylamino-benzo(b)bicvclo

L3.3.1llnona-3,6a(l0a)-diene (4.5 g) which is converted

using a saturated solution of hydrogenchloride in ether 0 to the hydrochloride (4.2 m.p. 250-252 C.

In the same manner the 11-anti-methylamino compound

is prepared as the HCl salt, m.p. 260 OC.

4 86,830

79,69 5 Example.XII

8-methoxy-11-amino-benzo(b)bicyclo[3.3.lloa36(0)

diene.HCl

8-Methoxy-ll-syn-formamido-benzo(b)bicyclo3.3.1]fona-

3,6a(lOa)-diene (4.0 g) is hydrolysed with potassium

hydroxide solution as described in Example II and the base

is treated with hydrogenchloride in ether solution to give

8-methoxy-1-syn-amino-benzo(b)bicylo[3. 0 g, m.p. 255-264 C.

In the same manner the corresponding anti-amino compound 0 is prepared HC1 salt 240 C) from the 8-methoxy-li-

anti-formamido compound.

Example XIII

8-methoxy-ll-dimethiamino-beno(b)bicycloi33.llnona3,6a

8-Methoxy-ll-syn-amino-benzo(b)bicyclo[3.3.1]nona-3,6a

hydrochloride (2.0 g) is treated with sodium

hydroxide solution and the free amine is isolated and

treated with formic acid and formaldehyde as described

in Example X. Treatment of the isolated product with

saturated hydrogenchloride in ether gives 8-methoxy-ll-

syn-dimethylamino-benzo(b)bicyclo[3.3.1]nona3Ga(loa)

diene hydrochloride (1.7 g) m.p. >2050 (decomp.).

In the same manner the 11-anti-dimethylamino compound

0 is prepared as the hydrochloride, melting point 260-261 C.

Example XIV

8-chloroll-methylamino-benzo(b)bicycloL3.3.1'lnona-3,6a

A solution of 8-chloro-ll-syn and 11-anti-formamido-

24 486,8

79, 69 benzo(b)bicyclo[3.3.lnona-3,6a(Oa).diene (3.5 g) in

dioxan is treated with lithiumaluminiunhydride as described

in Example VIII and the epimers separated by fractional

crystallisation of their hydrochlorides to give 8-chioro-

1l-syn-methylamino-benzo(h)bicyclo3.3.1]nona-3,6a(10a)-

diene hydrochloride (1.1 g) m.p. 2250 and 8-chloro-ll-

anti-methylamino-benzo )bicyclo{3.3.llnona-3,6a(10a)-

diene hydrochloride g) m.p. 220 0 C.

Reaction of these compounds with an acyl chloride,

namely acetylchloride, benzoylchloride, p.chlorobenzoyl-

chloride and phenylpropionylchloride respectively results

in the corresponding N-acetyl, N-benzoyl, N-p-chloro-

benzoyl and N-phenylpropionyl compound.

Example XV

8-chloro-ll-dimethylamino-benzo(b)bicyclol3.3*1'Inona-3,6a

and salts

A solution of 8-chloro-11-syn-methylamino-benzo(b)bi-

cyclo[3.3.1nona-3,6a(Oa)-diene hydrochloride (0.5 g) is

treated with alkali and the free base reacted with formic

acid and formaldehyde as described in Example IX. Treat-

ment of the free base with hydrogenchloride yields 8-chloro-

ll-syn-dimethylamino-benzo(b)bicyclot 3.3.1 nona-3,6aCl0a)-

diene hydrochloride (0.4 g) m.p. 200 0 C. Treatment of the

free base with maleic acid gives the maleate.

In the same manner the anti-dimethylamino-compound is

prepared, molting point HCl salt 193-198 0 C, starting from

the corresponding 8-chloro-1l-anti-methylamino compound.

4 86,830

79, 69 5,r75 Example XVI

In an analogous manner as described in the Examples

VIII, IX and X the followaing compounds are prepared:

8,9-ciichloro-11-syn-methylamino-benzo(b)bicyclo[3.3.1]nona-

3,

8,9-dichloro-ll-anti-methylamino-benzo(b)bicyclot3.3.1J

nona-3, Ga la)-diene .HCl.

8, 9-dichloro.-1l-syn-dimethylamino-benzo(b)bicyclo[3.3. 1]

nona-3 a(lOa)-di-ene.HClq

8-bromo-l l-anti-methylamino-benzo bicyclo ]nona- 3,6a(l0a) -diene.HC1, 8-methyl-ll-anti-methylamino-benzo bicycloL 3.3. llnona-

3 ,6a(l0a)-diene.HC1, 8-methyl--ll-syn-methylamino-benzo bicycloL3.*3 1jnona-

3 8-methyl-11-anti-dimethylamino-benzo bicyclo; 3.3.1 jnona- 3 ,6a(l0a)-diene.HC1,

8-methyl-11-syn-dimethylamino-benzo(b)bicycloL3.3.ljnona-

3 ,6a(lOa)-.diene.HC1,

8, 9-dimethoxy-ll-anti-methylamino-benzo (b)bicycloL 3.*3.1]

nona--3, Ga -diene .HCl,

9-chloro-11-anti-dimethylamino-benzo(b)bicycloL3.3.ljnona-

3 ,6a(10a)-diene.HCl,

9-chloro-11-syn-direthylamino-benzo(b)bic ycloL3.3.ljnona-

3 ,6a(10a)-diene.HCI,

8-chloro--9-CF 3 1-an ti-dimethylamino-benzo(b)bicyclo L3.3.lj

nona-3 ,6a Cba)-diene, 8-chloro-9-CF 3 -bb1-syn-dime'hybarnino-benzo(b)bicycloL3.3.bj

nona-3 a(b0a) -diene,

8-nitro-9-CF 3- b-dimethylamino-benzo(b)bicycloL3.3.1]

4 8 6,8 3(

7-9, 69 5 M7 nona-3 ,6a Cla) -diene, 8,10-dichloro-ll-anti-methylamino-benzo(b)bicyclo[3.3.1] nona-3, 6a Cla)-diene. 1-C1.

Examole XVII

8-methoxy-11-pyrr-olidino-benzo(b)bicyclot3.3.l inona-3,6a (l0a)-diene.HC1

8-Methoxy-benzo(b)bicycloL3.3.ljnona-3,6a(0a)-diele-

11-one (10 g) is treated .:ith formic acid (20 ml) and

pyrrolidine (40 ml) in an analogous manner as described, in

Exampl~e I. The crude product is chromatographed over sill-

cagel and the separate fractions are treated with saturated HCl in ether to give 3.5 g 8-methoxy-il-anti-pyrrolidino- 0 benzo(b)bicycloL3.3.llnona-3,6a(10a)-diene.HCl, m~p. >205 C and 1.2 g of the corresponding 11-sy 1 -p--yrrolidino- 0 compound, m.p. >195 C (dec.).

By using other amines instead of pyrrolidine the fol-

lowing compounds are prepared in a similar manner: 3 3 8-methoxy-11llsynpiperidino-benzo(b)bicycloL ilnona-

3,6a(l0a)-diene.fHC1, 3 3 8-methoxy-11-anti-piperidino-benzo(b)bicycloL ljnona-

3,

8-methoxy-11-syn-mlorpholino-belzo bicycloL 3.*3.1 jnona-

3,

8-methoxy-11-anti-morpholino-benzo(b)bicycloL3.3.linona- 3, 6aC l0a)-diene.HCl,

8-methoxy-11-anti-dimethylamilo-belzo bicyclot 3. 3.1]

nona-3,6a(10a)-diene.lialeate and HCl salt, 3 8-methoxy-11-syn-metbylamino-benzo~b)bicyclOL 3.ljnona-

3, 6a(l0a)-diene.1HCl,

4 86,830

7 ,9,695 8-methoxy-1l-phelylethylamiflo-benzo(b)bicyclo[3.3.ljnona- 3,6a(l0a)-diele (oil).

Example XVIII

In an analogou's manner as described in Example XVII for

the preparation of 8-methoxy-substituted benzobicyclonOnenes, also various unsubstituted benzobicyclononenes can be pre-

pared by reacting benzo(b)bicycloL3.3.lJnona-3,6a(l0a)- dien-ll-one (10 g) with formic acid and the desired amine

of formula III. The mixture of the syn- and anti-amino

compound thus obtained is optionally chromatographed over

silica and the separate-fractions treated with a saturated solution of an organic or inorganic acid in ether or alco- hol.

The following compounds are obtained in ihis manner:

1l-syn-dimethylamino-benzo bicycloL 3.3.1 jnona-3, Ga la)

dieneHC1,

11at-iehlmn-ez~~bccoL..]oa36(0) diene.H-C1,

11snmtyaiobnobbccO33.joa36(0) diene .HCl,

11-anti-methylamilo-benzo(b)bicycloL3.*3.1 Jnona-3, 6a la) diene. HCl,

11at--yrx-hnltyaiobnobbccO331 nona-3 ,6a (l0a)-diene.HCl,

11-syn-p-methoxyphenylethylaminobenzo(b)bicclOL33l] nona-3

11at---ehoyhnlty- -methylamino-benzo~b)bi-

cycloL3.3.ljflona3,6a(10a)diene.HClI

11 -phefylthylamiflo-benzo(b)bicycloL3.3.ljnona-3,6a(10a)-

28 4 86,83

79, 6 9 5 diene (oil),

ll-benzylamino-benzo(b)bicyclo[3.3.l]nona-3,6a(l0a)-diene

(oil).

Example XIX

In an analogous manner as described in Example XVII

various substituted benzo(b)bicyclof3.3.l]nona-3,6a(l0a)-

dien-ll-one derivatives are converted into the following

compounds using formic ac-id and an amine as reagents:

8-chloro-l1-syn-methylamino-benzo bicyclol3.3.1 mona-

3, 6a(10a)-diene.HC1,

8-chloro-ll-anti--methylamino-benzo Cb) bicyclol 3.3.1 ]nona-

3, Ga(10a)-diene.HCl, c

8-hoo1-y-iehlmn-bnobbcco33l-oa

3, 6a(l~a)-diene.HCl,

8-chloro-11-anti-dimethylamino-benzo(b)bicycloiL3.3.llnona-

3, 6a(lOa)-diene.HCl,

8-yrx-1sndmtyaiobnobbccoL..joa

3, 6a(l~a)-diene.HCl,

8,-iyrx-1sndmtyaiobnobbccO33l

nona-3 ,6a(l~a) -diene.HCl, 3 3 8,9-dimethoxy-11-anti-dimethylamino-benzo(b)bicYclOL .lj

nona-3,6a(10a)-diene.HCl,

8,9-dichloro-11-syn-dimethylamino-benzo(b)bicyclo[3.3.1]

nona-3 ,6a( l~a)-diene. HCl, 3 3 8-bromo-ll1.anti-methylamino-benzo(b)bicycloL linona-

3, 9-trifluoromethyl-1l-dimethylamino-benzo(b)bicyclOL3.3.1i

nona-3 ,6a (la)-diene,

8,10-dichloro-11-dimethylamino-benzo(b)bicyclOL3.3.lJflofa-

3,

29 486,8

79,695 8-chloro-ll-anti-ethylamino-benzo(b)bicyclo.3.3.1jnona-

3,6a(10a)-diene.HC1,

8-chloro-ll-anti-isopropylamino-benzo(b)bicyclo[33.1]

nona-3,6a(lOa)-diene.HCl,

8-chloro-ll-anti-cyclopentylamino-benzo(b)bicyclo[3.3.1

nona-3,6a(lOa)-diene.HCl,

8-chloro-ll-anti-pyrrolidino-benzo(b)bicyclo[3.3. lnona-

3,6a (Oa)-diene.HC1.

Example XX

11-amino-benzo(b)bicyclo[ 3.3.1 nona-3,6a(lOa)-diene.HC1

A mixture of 0.6 g benzo(b)bicycloL3.3.ljnona-3,6a(lOa)-

dien-11-one, 1.5 g hydroxylamine hydrochloride, 18 ml sodium-

hydroxide and 6 ml ethanol is refluxed for 4 hours. The

reaction mixture is cooled down and diluted with water. The

oily phase is then separated from the aqueous phase and the

oily phase is washed twice with water. The oily substance (the oxime) is then dissolved in

isopropanol, after which cautiously and portionwise about

2 g sodium is added. The mixture is stirred until the sodium

has been dissolved completely and then further stirred for

one additional hour. The reaction mixture is poured into

water (300 ml) and extracted with ether. The ether extracts

are collected and dried, after which the ether is evaporated,

yielding an oily substance consisting of a mixture of the

syn- and anti-amino compound. The oily substance is further

purified by distillation in vacuo.

The purified oil obtained is dissolved in ether and

treated with saturatedoHCl in ether, yielding a precip-

itate, that is isolated by filtration. The HC1 salt

4 86,83

79. 6 9 5 obtained is separated by a careful fractional crystalli-

sation giving the H'Cl salts of 11-anti- and li-syn-amino

di'astereo-isomers in pure state; melting points 2650 0 (subl.) and >28P C respectively.

In the same manner as described in previous examples

the 11-amino compound obtained may be alkylated to give

the corresponding li-methylamino and 11-dimethylamino compounds.

In the same manner ar~e prepared:

8-ehx-1snaiobnob~iylL..joa36(0) diene.HCl, 6 8-methoxy-11-anti-amino-benzo(b)bicyclOL3.3.linona-3, a -diene.HCl,

8-chloro-l11syl-amfino-belzo bicycloL 3.*3.1 ]nona-3, 6a la)

diene.HC1,

8-hoo1-niaiobnobbccoL..joa36(0) diene.HC1,

8,-iehx-1snaiobnz~~iyl'..joa36 Cl0a)-diene.HC1,

8,-iehx-1a-t-mn-bnobbcco33lnra 3,Ga(10a) -diene.HCl,

8-ehl1-y-mn-ez~~bccoL..joa36(0) diene.HC1,

8-ehl1-niaiobnob~iylL..joa36(0) diene.HCl.

Example XXI

11dmt laiobnobbcco3.3.1 jnona-3,6a(lOa)-

diene .HlC1 suspension of LiAllH in dry ether is caut iously and

4 86,830

79,6 9 5 n dropwise added to a solution of benzo(b)bicyclo3.3.l]nona- 3 6 a(10a)-dien-ll-one in ether/THF The mixture is stirred for 6 hours at ambient temperature. Then water is added to the mixture, after which the mixture is filtered

to remove the inorganic solids. The filtrate is evaporated,

and the oily residue washed with water and dried, yielding

a crude mixture of both diastereoisomers of 11-hydroxy-

benzo(b)bicyclo[3.3.1]nona-3,6a(10a)-diene

4 gram of this crude mixture is dissolved in dry pyri- dine. The solution is cooled on ice whereupon 5 g tosyl-

chloride is added. The mixture is stirred for 24 hours

and then poured into 400 ml water. The aqueous mixture

is then extracted into ether and the ether fractions

washed with water, 2 n HC1 and then washed neutral with

water. The ether solution is dried and evaporated, yiel-

ding an oily crude mixture of the diastereoisomers of 11-

tosyloxy-benzo(b)bicyclo[3.3.1nona-3,6a(lOa)-diene.

To the oily residue obtained, dissolved in dry di-

methylsulphoxide (50 ml), 15 ml dimethylamine is added. The mixture is heated on a steambath in a closed ampoule

for two hours. The mixture is then cooled, poured into 300 ml water, and extracted into ether. The ether extracts are washed and dried and then treated with saturated

solution of HC1 in ether. The hydrochlorides obtained are chromatographed over silica and then fractionally crystal- lised from methanol carefully yielding 11-syn-dimethyl-

amino-benzo(b)bicyclo[3.3.1]nona-3,6a(0a)-diene.HC1,

m.p. >230 C, and 1l-anti-dimethylamino-benzo(b)bicyclo

L3.3.1Jnona-3,6a(10a)-diene.HCl, m.p. 255-2590C (subl.).

32 4 86.83

79, 6_9 5 In the same manner are prepared: 3 8-methoxy-11-anti-pyrrolidilo-beflzo(b)bicycloL 3.ljnona-

3,6a(l~a) -diene.HCl,

8-methox<y-11-anti-morph-olilo-benzo(b)bicycloL3.3.ljnona- 3,6a(l0a)-diene.HC1,

8-chloro...ll.anti-yrrolidiflio-benzo bicyc.oL 3.3.1 mona-

3 ,6a(10a)-diene.HCl,

8-ehl1-nidmt~a-n-ez~~iylL..joa 3, 6a(lOa)-diene.HCl.

Example XXII

11-svn-PN-cyclopropylmethylamino-belzo(b)bicyclo! 3.3.llnona- 3, 6a(10a) -diene.HCl

ll-Syn-amino-benzo(b)bicycloL3.3.ljflofa3,6a(10a)-diene

(6.85 g) in toluene (35 ml) is treated with sodium bicar-

bonate (7.8 g) followed by a solution of cyclopropane-

carboxylic acid chloride (4.0 ml) in toluene (35 ml) and

the mixture is stirred for 6 h. The mixture is poured

into water, allowed to stand for 1 h and the product is

isolated using methylene chloride to give 11-syn-cyclo-

propane carboxamido-benzo(b)bicycloL3.3.lJnona-3,6a(10a)- diene (7.2 g).

A suspension of LiAlH 4 (1.6 g) in dry tetrahydrofuran

ml) is dropwise added to a stirred solution of 7.2 g

of the above product, dissolved in 60 ml ,arm tetrahydro-

furan, after which the reaction mixture is stirred for

h. The mixture is then cooled and water (6 ml) sodium

hydroxide solution (6 ml; 4M) and water (18 ml) are added.

The mixture is filtered, the filtrate diluted with water

and the product isolated by extracting with ether. The et'her

4 86830

79,69 is evaporated and the residue dissolved and chromatographed

over silica.

Treatment of the residue after removal of solvent with

a saturated solution of hydrogen chloride in ether gives

ll-syn-N-cyclopropylmethylamino-benzo(b)bicycloL.3.3.1]

nona-3,6a(10a)-diene.HCl, melting point >2300 C.

In a similar manner the following compounds are

prepared:

8-chloro-1 l-anti-N-cyclopropylmethylamino-benzo (b)bicyclo

L 3.3. 1]nona-3,6a (10a) -diene.HC1, 8-chloro-11-anti-N-ethylamino-benzo(b)bicyclo[3.3.ljnona-

3, 6a C a) -diene hydrochloride,

8-methoxy-ll-syn-N-cyclopropylmethylamino-benzo bicyclo

L3.3.ljnona-3,6a(10a)-diene.HC1, 11-syn-N-p-methoxyphenethylamino-benzo(b)bicyclo.3.3.lj nona-3, 6a (10a)-diene. HCl,

1 l-anti-N-p-hydroxyphenethylamino-benzo bicycloL 3.*3 1

nona-3 6a (10~a) -diene. HC1,

8-chloro-ll--anti-N-p-metboxyphenethylamino-benzo (b)bicyclo

[3.3.ljnona-3,6a(10a)-diene.HC1.

Starting from the appropriate ll-methylamino derivatives

the following compounds are prepared in a similar manner:

11-anti-N-cyclopropylmethyl-N-methylamino-benzo(b) bicyclo

L3.3.lJnona-3,6a(lGa)-diene hydrochloride, 1 l-syn-N--cyclopropylmethyl-N-methvlamino-ben zo bicyclo

L3.3.ljnona-3,6a(l0a)-diene citrate, and the corre- sponding HCl salt,

11-ant i-N-p-methoxyphenethyl-N-methylamino-benzo bicyclo

L3.3.1]nona-3,G6a(10a)-diene.HC1,

34 4 86830

79,69 5 1l-anti-N-p-hydroxyphenethyl-N-methylamino-benzo(b)bicyclo

13.3.lJnona-3,6a(la)-diene.HC1,

11-syn-N-p-chlorophenethyl-N-methylamino-benzo(b)bicyclo

L3.3.ljnona-3,6a(10a)-diene.HC1,

1l-anti-N-p-chlorophenethyl-N-methylamino-benzo(b)bicyclo

L3.3.ljnona-3,6a(10a)-diene.HCl.

Example XXIII

1l-syn-N-o-hvdroxvnhenethvl-N-methylamino-benzo(b)bicvclo

03.3.lnona-3,6a(la)-diene.HCl

1l-Syn-N-p-methoxyphenethyl-N-methylamino-benzo(b)bi- 0 cyclo[3.3.lJnona-3,6a(lOa)-diene hydrochloride (4.12 g)

was added to fused pyridine hydrochloride (25 g) at 170-

2100 C and the mixture was stirred for 30 min. The solution

was cooled, water (25 ml) was added followed by solid

sodium bicarbonate (1.1 The precipitated solid was

filtered off, washed with a little water and re-crystal-

lised from methanol/ether to give 1l-syn-N-p-hydroxyphen-

ethyl-N-methylamino-benzo(b)bicycloL3.3.ljnona-3,6a(10a)- 0 diene hydrochloride 2.41 g, m.p. 260-266 C.

Example XXIV

8-hydroxv-ll-syn-dimethvlamino-benzo(b)bicvclo 3.3.1 nona-

3,6a(Oa)-diene.HC1 3 3 8-Methoxy-l-syn-dimethylamino-benzo(b) biccloL -li

nona-3,6o(lOa)-diee.hydrochloride (11 g) is heated with

fused pyridine hydrochloride (87 g) at 170-220 0 C under

nitrogen for 15 min, whereupon the mixture is cooled and

water is added. The pH is adjusted to 12 by addition of

solid sodium bicarbonate and the product is isolated using

4 86,830

7 9,69-~5n'5 methylene chloride and treated with a saturated solution

of hydrogen chloride in methylene chloride to give 8-

hydroxy-11-syn-dimethylamino-benzo(b)bicycloi3.3.1]nona- 3,6a(l0a)-diene.HCl, melting point >2400 C.

The following compounds are prepared in a similar

manner: 8-hydroxy-11-syn-amino-benzo(b)bicyclo[3.3.1]nona-3,Ea

(l0a)-diene hydrochloride, 8-hydroxy-ll-anti-amino-benzo bicycloL3.*3. ljnona-3 a

(l0a) -diene hydrochloride.

4 86,830

Claims (4)

79,695-n5 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A compound of the general formula:

and salts thereof, in which R1 and R2 stand for

hydrogen, alkyl, alkenyl, optionally substituted aralkyl

or acyl, or R1 R 2 together with the nitrogen atom

represent a saturated heterocyclic 5- or 6-membered

ring, and X and Y stand for hydrogen, hydroxy, halogen,

alkyl (1-6 alkoxy (1-6 nitro, trifluoromethyl

or acyloxy.

2. A compound according to claim 1, in which

R and R 2 stand for hydrogen or methyl.

3. A compound according to claim 1, of the

formula:

in which Hal stands for chloro or bromo and n 1 or

2.

4. Process for the preparation of benzobicyclo-

nonenes of the general formula I as defined in claim 1

and salts thereof, characterised in that a compound of

the general formula II:

in which X and Y have the meanings indicated in claim 1,

is reacted with formamide, N-alkylformamide, N,N-dialk-

ylformamide or an amine of the general formula. III:

no 4 86,830

79,695

I- H I or a salt thereof,

in which R' and R' have the same meanings as R 1 and

R 2 defined in claim 1 with the exception of an acyl

moiety, in the presence of a reducing agent, after

which the compound thus obtained, in which R1 is

formyl, may be hydrolysed to obtain the corresponding

compound in which R is hydrogen, or may be reduced

to obtain the corresponding compound in which R1 is

methyl, and/or the compound thus obtained in which at

least one of the moieties R1 or R 2 is hydrogen may be

alkylated, alkenylated, aralkylated, acylated or acylated

followed by reduction of the N-acyl moiety to obtain

the corresponding compound in which the said hydrogen

has been replaced by alkyl, alkenyl, optionally

substituted aralkyl or acyl, and/or the compound thus

obtained in which X and/or Y is methoxy may be hydrolysed

to obtain the corresponding compound in which X and/or

Y is hydroxy, ,and/or the compound thus obtained may be

converted into a pharmaceutically acceptable salt thereof,

on the understanding that either before or after these

aforesaid subsequent reactions the compound obtained

may be separated into the separate diastereo-isomers

thereof and/or the separate enantiomers thereof.

Process according to claim 4, characterized

in that the reducing agent is formic acid.

6. Process for the preparation of benzo cyclo-

nonenes of the general formula I as defined in claim 1

and salts thereof, characterized in that the imine- 4 86,830

79,69 5

moiety of a compound of the general formula IV:

i-

or a salt thereof, in which X and Y have the meanings

indicated in claim 1 and R stands for hydrogen, hydroxy, alkoxy alkyl (1-6C) or an optionally substituted

aralkyl group, is reduced, after which the compound thus obtained may be alkylated, alkenylated, aralalkylated,

acylated or acylated followed by reduction of the N-acyl

moiety, and/or a compound thus obtained in which X and/or

Y is methoxy may be hydrolysed to obtain the corresponding

compound in which X and/or Y is hydroxy, and/or the

compound thus obtained may be converted into a

pharmaceutically acceptable salt thereof, on the

understanding that either before or after these aforesaid

subsequent reactions the compound obtained may be separated

into the separate diastereo-isomers and/or separate

enantiomers thereof.

7. Process for the preparation of benzobicyclonon-

nenes of the general formula I as defined in claim 1 and

salts thereof, characterised in that a compound of the

general formula VA:

in which X and Y have the meanings indicated in claim

1 and R 4 stands for halogen or an etherified or esterified

hydroxyl group (leaving group) is reacted with an

4 86,830

79, 69 5

amine of the general formula III or a salt thereof, in

which R' and R' have the same meanings as R and R2 defined in claim 1 with the exception of an acyl group,

after which the compound thus obtained in which at least

one of the moieties R or R 2 is hydrogen, may be

alkylated, alkenylated, aralkylated, acylated or acylated

followed by reduction of the N-acyl moiety to obtain

the corresponding compound in which the said hydrogen has

been replaced by alkyl, alkenyl, optionally substituted

aralkyl or acyl, and/or the compound thus obtained in

which X and/or Y is methoxy may be hydrolysed to obtain

the corresponding compound in which X and/or Y is hydroxy,

and/or the compound thus obtained may be converted into a

pharmaceutically acceptable salt thereof, on the under-

standing that either before or after the aforesaid

subsequent reactions the compound obtained may be separated

into the separate diastereo-isomers thereof and/or the

separate enantiomers thereof.

8. A pharmaceutical composition exerting anorectic

and antidepressant activities comprising a compound of

the general formula I defined in claim 1 and one or more

pharmaceutically.acceptable carriers or diluents.

9. Process for treating obesity and depression

comprising the administration of a daily dosage of from

0.005 mg to 50 mg per kg body weight of a compound of

the general formula as claimed in claim 1.

A process according to claim 4, 6 or 7

substantially as hereinbefore described with reference

to any one of the foregoing examples.

4 86,83

79,695

11. A compound according to claim 1 substantially

as hereinbefore described with reference to anyone of

the foregoing examples.

DATED THIS DAY OF SEPTEMBER, 1977.

AKZO N.V. By Its Patent Attorneys

CLEMENT HACK CO. Fellows Institute of Patent Attorneys of Australia.

4 86,830